Typhoid is endemic in many parts of southeast Asia. Due to the
resistance of the organism to first line of antibiotics (ampicillin,
chloramphenicol, cotrimoxazole) as well as to fluoroquinolones, third
generation cephalosporins have been in use for the empiric treatment of
typhoid for years. However an increasing incidence of Salmonella Typhi
is being reported sporadically from various regions. We report a case of
typhoid due to Salmonella Typhi which was non-responsive to treatment
with a cephalosporin, was found to be multidrug resistant and resistant
to ciprofloxacin and third generation cephalosporin as well. The patient
was finally treated successfully with intravenous administration of a
carbapenem.

Keywords: Typhoid fever, Salmonella Typhi, cephalosporin,
carbapenem.

Introduction

Typhoid fever is a common and serious infectious disease endemic in
many parts of Southeast Asia.1 The disease is associated with high rates
of morbidity and mortality and requires appropriate antimicrobial
therapy for successful clinical outcomes. Rising drug resistance is
becoming a major issue in the treatment of enteric fever. Consequent to
the emergence of multidrug resistance and resistance to quinolones,
cephalosporins became the forefront for the treatment of typhoid.2
However, an evidence of rising MICs to cephalosporins and production of
Extended Spectrum Beta lactamases (ESBLs) by Salmonella enteric serovar
Typhi is emerging. Resistance to cephalosporins occurs due to the
production of extended spectrum Beta lactamases (ESBLs) by the organisms
and have been detected in various organisms of the family
Enterobacteriacae.

The genes for the production of ESBLs are carried on plasmids or
transposons and may be transferred to other members of the family, hence
making them resistant to cephalosporins. This is an extremely alarming
situation as the dissemination of these resistant organisms will further
limit the therapeutic options for treating typhoid.

We report a case of typhoid due to Salmonella enteric serovar Typhi
which was resistant to all the first line antibiotics as well as
fluoroquinolones and third generation cephalosporin. Hence the patient
had to be treated with meropenem, a carbapenem drug which is not usually
recommended for the treatment of typhoid fever.

Case Report

A previously healthy 17 years old male presented to the hospital
with 14 days history of continuous, high grade fever with rigors and
chills, headache and fatigue. There was no history of diarrhoea or
constipation. At the time of admission, he was febrile with temperature
39C, looked unwell and was found mildly dehydrated. On examination,
abdomen was tender and spleen was palpable 3 cm below the left costal
margin. On auscultation, he had bradycardia (heart rate 56 beats/min)
and bowel sounds were present. Blood examination showed Haemoglobin of
8.7 g/dl, total leukocyte count was 3.3X109/L and C-reactive protein was
positive. The LFTs and serological markers for acute viral hepatitis
were normal. Urinalysis and stool examination revealed no abnormality.
Ultrasound of abdomen showed an enlarged spleen with a few enlarged
mesenteric lymph nodes. His past history was unremarkable. He was
provisionally diagnosed as a case of typhoid.

Blood and stool were collected for culture and the patient was put
on injection ceftriaxone 2gram intravenous stat and then continued as
1gram IV twice daily. The patient was discharged on request with advice
to continue treatment in out patient department. Meanwhile blood culture
revealed the growth of multidrug resistant (ampicillin, cotrimoxazole,
chloramphenicol) Salmonella Typhi which was also resistant to
ciprofloxacin, azithromycin, aztreonam, gentamicin and ceftriaxone, was
an ESBL producer and sensitive only to meropenem. The patient was
recalled who was still having fever despite treatment. Physical
examination at the time of readmission revealed a body temperature of
>39C and pulse rate of 120/minute. Abdomen was diffusely tender with
increased bowel sounds. Keeping in view the sensitivity report the
patient was put on Injectable Meropenem 1 gram 8 hourly. He continued to
have high grade fever (>39C) for 3 days and then remained febrile for
only one day with temperature less than 39C.

His general condition became better and his appetite improved.
Repeat blood and stool culture were negative. Keeping in view the high
resistance of the isolate Injection Meropenem was continued for 7 more
days.

The patient was discharged from the hospital 10 days after admission
when he had fully recovered, was afebrile and was feeling well.

Discussion

With the emergence of resistance to ampicillin, cotrimoxazole and
chloramphenicol, ciprofloxacin became the drug of choice for treating
typhoid. However, a rising resistance to ciprofloxacin reported from
various regions lead to decreased use of fluoroquinolones as empiric
treatment of typhoid. The option left was to use either azithromycin or
a third generation cephalosporin. The isolate from our patient was
resistant to both of these antimicrobials as well. Resistance to 3rd
generation cephalosporins has also been reported from other countries.
Sarika Jain et al1 carried out a study on 344 strains of Salmonella and
resistance to 3rd generation cephalosporin was observed in 7(2%) strains
of Salmonella Typhi. A single cephalosporin resistant ESBL (and
transferable among Enterobacteriacae) producing Salmonella Typhi was
isolated from Japan in 2010.3 First ESBL producing Salmonella Typhi from
Bangladesh was reported in 20124 and has also been reported from
Phillipines.5

Yvonne et al6 reported a cephalosporin resistant, ESBL producing
Salmonella Typhi from the blood of an Iraqi woman in Germany. Amna et
al., carried out a study in Faisalabad, Pakistan, on 30 isolates of
Salmonella Typhi and found an emerging resistance to cephalosporins,
however, no ESBL producing strain was detected.7 In a recent study
carried out in Bangladesh, twenty four Salmonella Typhi isolates from
stool culture of typhoid patients were resistant to ceftriaxone.8

The spread of ESBL producing strains of Salmonella Typhi conferring
resistance to broad spectrum cephalosporins is worrisome as their spread
may seriously limit therapeutic options for treating typhoid. The high
resistance to first line antimicrobials, fluoroquinolones and resistance
to third generation cephalosporins will leave us with no option but to
resort to carbapenems and tigycyclines for empiric treatment of typhoid.
This in turn can have serious implications for empiric antimicrobial
therapy in a country where typhoid is endemic.